The ability of mitochondria to oxidatively synthesize ATP from ADP and inorganic phosphate is compromised in the failing heart. Specifically, the magnitude of the free energy at which ATP is synthesized in heart failure is diminished compared to control. However the causal mechanisms involved are not clearly understood. Here we used computer simulation to analyze the impact of reduction in three cytoplasmic metabolic pools that is observed with hypertrophic remodeling and heart failure. Our simulations, which are validated based on in vivo data on phosphate metabolites in both the healthy and diseased heart, predict that, given a prescribed reduction in the total adenine nucleotide pool, the pools of total creatine and total exchangeable phosphate are maintained at levels that maintain the ATP hydrolysis potential of the heart at near the normal physiological value.